G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo
Abstract Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease b...
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Springer Nature
2017-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201707850 |
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| author | Roberto Simone Rubika Balendra Thomas G Moens Elisavet Preza Katherine M Wilson Amanda Heslegrave Nathan S Woodling Teresa Niccoli Javier Gilbert‐Jaramillo Samir Abdelkarim Emma L Clayton Mica Clarke Marie‐Therese Konrad Andrew J Nicoll Jamie S Mitchell Andrea Calvo Adriano Chio Henry Houlden James M Polke Mohamed A Ismail Chad E Stephens Tam Vo Abdelbasset A Farahat W David Wilson David W Boykin Henrik Zetterberg Linda Partridge Selina Wray Gary Parkinson Stephen Neidle Rickie Patani Pietro Fratta Adrian M Isaacs |
| author_facet | Roberto Simone Rubika Balendra Thomas G Moens Elisavet Preza Katherine M Wilson Amanda Heslegrave Nathan S Woodling Teresa Niccoli Javier Gilbert‐Jaramillo Samir Abdelkarim Emma L Clayton Mica Clarke Marie‐Therese Konrad Andrew J Nicoll Jamie S Mitchell Andrea Calvo Adriano Chio Henry Houlden James M Polke Mohamed A Ismail Chad E Stephens Tam Vo Abdelbasset A Farahat W David Wilson David W Boykin Henrik Zetterberg Linda Partridge Selina Wray Gary Parkinson Stephen Neidle Rickie Patani Pietro Fratta Adrian M Isaacs |
| author_sort | Roberto Simone |
| collection | DOAJ |
| description | Abstract Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA‐binding proteins and through toxic dipeptide repeat proteins generated by repeat‐associated non‐ATG translation. GGGGCC repeat RNA folds into a G‐quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G‐quadruplex RNA. We investigated their effect in C9orf72 patient iPSC‐derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat‐expressing Drosophila. Therefore, small molecules that target GGGGCC repeat G‐quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS. These data provide proof of principle that targeting GGGGCC repeat G‐quadruplexes has therapeutic potential. |
| format | Article |
| id | doaj-art-1f8b61ee6cea4757929c90eeb5c2d015 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-1f8b61ee6cea4757929c90eeb5c2d0152025-08-20T03:43:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-11-01101223110.15252/emmm.201707850G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivoRoberto Simone0Rubika Balendra1Thomas G Moens2Elisavet Preza3Katherine M Wilson4Amanda Heslegrave5Nathan S Woodling6Teresa Niccoli7Javier Gilbert‐Jaramillo8Samir Abdelkarim9Emma L Clayton10Mica Clarke11Marie‐Therese Konrad12Andrew J Nicoll13Jamie S Mitchell14Andrea Calvo15Adriano Chio16Henry Houlden17James M Polke18Mohamed A Ismail19Chad E Stephens20Tam Vo21Abdelbasset A Farahat22W David Wilson23David W Boykin24Henrik Zetterberg25Linda Partridge26Selina Wray27Gary Parkinson28Stephen Neidle29Rickie Patani30Pietro Fratta31Adrian M Isaacs32Department of Neurodegenerative Disease, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of NeurologyDepartment of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College LondonDepartment of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College LondonDepartment of Neurodegenerative Disease, UCL Institute of NeurologyMRC Centre for Neuromuscular Disease, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of Neurology‘Rita Levi Montalcini’ Department of Neuroscience, ALS Centre, University of Turin‘Rita Levi Montalcini’ Department of Neuroscience, ALS Centre, University of TurinDepartment of Molecular Neuroscience, UCL Institute of NeurologyNeurogenetics Unit, UCL Institute of NeurologyDepartment of Chemistry, Georgia State UniversityDepartment of Chemistry, Georgia State UniversityDepartment of Chemistry, Georgia State UniversityDepartment of Chemistry, Georgia State UniversityDepartment of Chemistry, Georgia State UniversityDepartment of Chemistry, Georgia State UniversityDepartment of Molecular Neuroscience, UCL Institute of NeurologyDepartment of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College LondonDepartment of Molecular Neuroscience, UCL Institute of NeurologyUCL School of PharmacyUCL School of PharmacyDepartment of Molecular Neuroscience, UCL Institute of NeurologyMRC Centre for Neuromuscular Disease, UCL Institute of NeurologyDepartment of Neurodegenerative Disease, UCL Institute of NeurologyAbstract Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA‐binding proteins and through toxic dipeptide repeat proteins generated by repeat‐associated non‐ATG translation. GGGGCC repeat RNA folds into a G‐quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G‐quadruplex RNA. We investigated their effect in C9orf72 patient iPSC‐derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat‐expressing Drosophila. Therefore, small molecules that target GGGGCC repeat G‐quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS. These data provide proof of principle that targeting GGGGCC repeat G‐quadruplexes has therapeutic potential.https://doi.org/10.15252/emmm.201707850amyotrophic lateral sclerosisC9orf72frontotemporal dementiaG‐quadruplex |
| spellingShingle | Roberto Simone Rubika Balendra Thomas G Moens Elisavet Preza Katherine M Wilson Amanda Heslegrave Nathan S Woodling Teresa Niccoli Javier Gilbert‐Jaramillo Samir Abdelkarim Emma L Clayton Mica Clarke Marie‐Therese Konrad Andrew J Nicoll Jamie S Mitchell Andrea Calvo Adriano Chio Henry Houlden James M Polke Mohamed A Ismail Chad E Stephens Tam Vo Abdelbasset A Farahat W David Wilson David W Boykin Henrik Zetterberg Linda Partridge Selina Wray Gary Parkinson Stephen Neidle Rickie Patani Pietro Fratta Adrian M Isaacs G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo EMBO Molecular Medicine amyotrophic lateral sclerosis C9orf72 frontotemporal dementia G‐quadruplex |
| title | G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo |
| title_full | G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo |
| title_fullStr | G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo |
| title_full_unstemmed | G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo |
| title_short | G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo |
| title_sort | g quadruplex binding small molecules ameliorate c9orf72 ftd als pathology in vitro and in vivo |
| topic | amyotrophic lateral sclerosis C9orf72 frontotemporal dementia G‐quadruplex |
| url | https://doi.org/10.15252/emmm.201707850 |
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